The overall aim of this application is to better understand the role of impaired glucagon suppression in the mechanisms that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various diverse mechanisms that drive the progression of prediabetes to diabetes. We have discovered an effect of diabetes-associated variation in TCF7L2 on glucagon suppression. The product of this locus is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. In addition, ?-cell function as quantified by the Disposition Index (DI) is also impaired. We propose to examine the temporal relationship of the effects of this locus on ?-cell and on ?-cell function in people with normal glucose tolerance or prediabetes to help examine if impaired glucagon suppression contributes to an increased rate of ?-cell dysfunction or if the two processes develop independently. Since ?-cell dysfunction has previously been overlooked in the pathogenesis of prediabetes, we will harness the Mayo Autopsy resource to examine islet morphology in humans with and without diabetes-associated variation at this locus. Our preliminary data suggests that ?-cell size and glucagon expression is increased in subjects with the T-allele at rs7903146 in the TCF7L2 locus. Finally we hope to improve the ability of the oral minimal model ? the gold standard used to measure ?-cell function in vivo ? to measure glucose homeostasis by incorporating a component that describes glucagon secretion and action. This will help elucidate the mechanism by which TCF7L2 leads to type 2 diabetes in humans but will also provide insights into the role of glucagon in the pathogenesis of prediabetes and progression to diabetes.

Public Health Relevance

Genome-wide association studies have identified multiple common genetic variants that predispose to type 2 diabetes. Of these genetic variation in TCF7L2 has the strongest effect on diabetes risk. However, its direct effects on glucose metabolism and on progression to diabetes are poorly understood. We have recently used diabetes-associated variation in this locus to demonstrate that impaired suppression of glucagon is an overlooked part of the mechanisms driving the conversion of prediabetes to diabetes. We propose to understand how this arises from studies examining temporal changes in glucagon suppression. We will also examine ?-cell morphology and propose a novel method to measure glucagon secretion and action in vivo. These studies will improve our ability to target prevention strategies to predisposed individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK116231-02
Application #
9571012
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2017-09-25
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Vella, Adrian; Matveyenko, Aleksey (2018) Walking a fine line between ?-cell secretion and proliferation. J Biol Chem 293:14190-14191
Sharma, Anu; Varghese, Ron T; Shah, Meera et al. (2018) Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans. J Clin Endocrinol Metab 103:314-319
Karanth, Santhosh; Adams, J D; Serrano, Maria de Los Angeles et al. (2018) A Hepatocyte FOXN3-? Cell Glucagon Axis Regulates Fasting Glucose. Cell Rep 24:312-319